Open AccessChemogenomic profiling in yeast reveals antifungal mode-of-action of polyene macrolactam auroramycin
Author(s) -
Jin Huei Wong,
Mohammad Alfatah,
Kiat Whye Kong,
Shawn Hoon,
Wan Lin Yeo,
Kuan Chieh Ching,
Corinna Jie Hui Goh,
Mingzi M. Zhang,
Yee Hwee Lim,
Fong Tian Wong,
Prakash Arumugam
Publication year - 2019
Publication title -
plos one
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.99
H-Index - 332
ISSN - 1932-6203
DOI - 10.1371/journal.pone.0218189
Subject(s) - yeast , cryptococcus neoformans , candida albicans , biology , candida tropicalis , mode of action , biochemistry , polyene , microbiology and biotechnology , aspergillus nidulans , streptomyces , chemistry , bacteria , gene , genetics , mutant
In this study, we report antifungal activity of auroramycin against Candida albicans , Candida tropicalis , and Cryptococcus neoformans . Auroramycin, a potent antimicrobial doubly glycosylated 24-membered polyene macrolactam, was previously isolated and characterized, following CRISPR-Cas9 mediated activation of a silent polyketide synthase biosynthetic gene cluster in Streptomyces rosesporous NRRL 15998. Chemogenomic profiling of auroramycin in yeast has linked its antifungal bioactivity to vacuolar transport and membrane organization. This was verified by disruption of vacuolar structure and membrane integrity of yeast cells with auroramycin treatment. Addition of salt but not sorbitol to the medium rescued the growth of auroramycin-treated yeast cells suggesting that auroramycin causes ionic stress. Furthermore, auroramycin caused hyperpolarization of the yeast plasma membrane and displayed a synergistic interaction with cationic hygromycin. Our data strongly suggest that auroramycin inhibits yeast cells by causing leakage of cations from the cytoplasm. Thus, auroramycin’s mode-of-action is distinct from known antifungal polyenes, reinforcing the importance of natural products in the discovery of new anti-infectives.